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Collateral assessment on magnetic resonance imaging/angiography up to 30 hours after stroke onset
Collateral assessment on magnetic resonance imaging/angiography
https://orcid.org/0000-0001-9680-1723
Tomari Shinya Conceptualization Data curation Formal analysis Investigation Methodology Resources Validation Writing – original draft 1 *
Lillicrap Thomas Data curation 1
Garcia-Esperon Carlos Data curation 1 2 3
Tomari Kashida Yumi Methodology 1
Bivard Andrew Supervision Validation Writing – review & editing 4
Lin Longting Data curation 1
Levi Christopher R. Conceptualization Supervision 1 2 3
https://orcid.org/0000-0002-9023-6177
Spratt Neil J. Methodology Project administration Supervision Validation Visualization Writing – review & editing 1 2 3
1 Hunter Medical Research Institute, Newcastle, Australia
2 Department of Neurology, John Hunter Hospital, Newcastle, Australia
3 College of Health, Medicine, and Wellbeing, University of Newcastle, Newcastle, Australia
4 Melbourne Brain Center at the Royal Melbourne Hospital, University of Melbourne, Parkville, Australia
Meckel Stephan Editor
RKH Klinikum Ludwigsburg, GERMANY
Competing Interests: The authors have declared that no competing interests exist.

* E-mail: sny5588@gmail.com
3 9 2024
2024
19 9 e030977910 4 2024
19 8 2024
© 2024 Tomari et al
2024
Tomari et al
https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Purpose

We aimed to validate hyperintense vessel sign (HVS) on FLAIR imaging or posterior cerebral artery (PCA) laterality on MR angiography beyond 4.5 hours after stroke onset.

Materials and methods

Data from acute ischemic stroke patients with internal carotid or middle cerebral artery occlusion who underwent CT perfusion imaging at baseline, follow-up MR perfusion imaging and angiography within 30 hours after stroke, without effective recanalization on follow-up imaging, were analysed retrospectively. Patients were separately classified as high or low HVS (>5 or ≤5 slices of HVS), and PCA laterality positive or negative group. We compared core and penumbra volumes at follow-up imaging and neurological outcomes between high or low HVS group, and between PCA laterality positive or negative group.

Results

Of 49 patients analyzed, four patients with artifacts were excluded and 45 were classified into high (n = 23) or low (n = 22) HVS group. High group had a smaller core volume (median 32 ml versus 109 ml, p = 0.004), larger penumbra volume at follow-up (68 ml versus 0 ml, p = 0.001), and better outcomes (modified Rankin Scale at three months, 3 versus 5, p = 0.03). For PCA laterality analysis, 1 patient with previously occluded PCA was excluded and 48 patients were classified as positive (n = 22) or negative (n = 26). Positive group had larger core volume (116 ml versus 37 ml), and no significant differences in penumbral volumes or outcomes.

Conclusion

Prominent HVS in later time was associated with small core volume, persistent penumbra volume and favorable outcomes.

The author(s) received no specific funding for this work. Data AvailabilityAll relevant data are within the manuscript and its Supporting Information files.
Data Availability

All relevant data are within the manuscript and its Supporting Information files.
==== Body
pmcIntroduction

The time window for thrombectomy extends up to 16–24 hours from symptom onset for ischemic stroke patients with persistent target mismatch [1, 2]. Patients with good collateral status are likely to have persistent target mismatch and previous studies reported collateral status grading based on computed tomography (CT) angiography [3, 4] or continuous parameters calculated with perfusion imaging such as hypoperfusion intensity ratio [5] or CT perfusion collateral index (CTPCI) [6]. Collateral assessment on magnetic resonance imaging (MRI) such as hyperintense vessel sign (HVS) on fluid-attenuated inversion recovery (FLAIR) [7, 8] or posterior cerebral artery (PCA) laterality on magnetic resonance angiography (MRA) [9] has been previously reported to be associated with good collateral supply.

HVS represents retrograde blood flow through the leptomeningeal anastomosis (LMA) during acute ischemic stroke [7, 8], and prominent HVS has been associated with good collateral flow, small core volume and favorable neurological outcomes [10, 11]. One or more vessel segments observable in PCA P4 segment beyond the extent of filling seen in the contralateral PCA represents the existence of collateral flow from the PCA via the LMA (PCA laterality) [9] and the presence of the laterality before thrombolysis predicts good recanalization and favorable outcomes [12]. Both signs were evaluated within 4.5 hours after stroke onset. Increasingly, patients presenting in later time windows are considered for EVT, or late-window thrombolysis, so it is important to know whether these MRI signs may be useful beyond 4.5 hours. We aimed 1) to identify acute ischemic stroke patients with HVS or PCA laterality between 4.5 hours and 30 hours after stroke onset, and 2) to compare core and penumbra volumes at follow-up imaging and neurological outcomes between those with or without prominent HVS and those with positive or negative PCA laterality.

Methods

Population and data collection

We retrospectively identified patients from our prospectively collected data base of acute ischemic stroke patients presenting to the John Hunter Hospital (New South Wales, Australia) from 1st June 2009 to 30th July 2017. Selected patients underwent acute CT perfusion imaging at baseline (within 6 hours after stroke onset or last seen well), with follow-up MR perfusion and angiography within 30 hours after stroke. We included patients who had acute large vessel occlusion (internal carotid artery (ICA) isolated occlusion or tandem occlusion, or MCA segment 1 or segment 2 proximal portion, without effective recanalization between baseline and follow-up imaging. Patients with M3 or distal occlusion or those with ICA/MCA occlusion successfully revascularized by thrombolysis or thrombectomy were excluded. Assessment of recanalization was made using the modified thrombolysis in cerebral infarction (mTICI) grade, with assignments of 0 (no recanalization), 1 (minimal recanalization), 2a (partial recanalization with less than 50%), 2b (partial recanalization with more than 50%) and 3 (complete recanalization). Effective recanalization was defined as mTICI 2b to 3. Patients with previously occluded PCA were excluded from PCA laterality assessment. We recorded clinical characteristics (age, sex, National Institute of Health Stroke Scale (NIHSS) at baseline and follow-up (assessed at 24─72 hours after onset), risk factors) for enrolled patients. The study was conducted in accordance with national guidelines and had institutional ethical approval as part of INSPIRE research (HNELHD HREC Reference No: 11/08/17/4.01). An opt-out consent process was followed. The data were accessed on the 30th October 2022 for research purposes. Authors had access to information that could identify individual participants during or after data collection.

Neuroimaging

Baseline CT

CT imaging was derived from 320-slice Aquilion ONE scanner (Canon medical systems, Otawara, Japan). Image scanning started 7 seconds after intravenous injection (40 ml, injected at 6ml/s) of non-ionic iodinated contrast (Ultravist 370; Bayer HealthCare, Berlin, Germany). It lasted for 60 seconds, acquiring 19 images per slice.

Follow-up MR image

MR imaging was performed on a 1.5- Tesla scanner (Siemens Avanto, Erlangen, Germany) and included axial isotropic diffusion weighted image (DWI), FLAIR image, time of flight magnetic resonance angiography, and bolus-tracking perfusion-weighted imaging. Following a bolus of gadolinium contrast (Magnevist; Bayer HealthCare, Berlin, Germany) into the antecubital vein (0.2 mmol/kg, injected at speed of 5 ml/s). The scanning lasted for 60 seconds, resulting in 40 images per slice. A total 19 slices were obtained.

Perfusion image analysis

CT perfusion and MR perfusion imaging was post-processed using the commercial software MIStar (Apollo Medical Imaging Technology, Melbourne, Australia) to generate automated core-penumbra maps. Penumbra was defined as tissue with a Delay Time (DT) >3 seconds and relative cerebral blood flow (CBF) ≥30% of the contralateral hemisphere, using either CT perfusion or MR perfusion imaging in MIStar [13]. DT is an index of time to the peak of the residual function, similar to Tmax. Ischemic core was defined as the tissue with a DT >3 seconds and a relative CBF <30% of the contralateral hemisphere on CTP, or an apparent diffusion coefficient threshold of <620×10−6 mm2/s on MR-DWI. All images were reprocessed and analysed using the same version of the MIStar software (Version 3.2 release 3.2.62.03, last update October 2019)

HVS and PCA laterality assessment

We focused on standard 5-mm-thick FLAIR images in the axial/horizontal plane with an intersection gap of 2 mm. We defined HVS as linear hyperintensities relative to gray matter in the MCA-territory. Punctiform hypersignals were not regarded as HVS. The HVS were differentiated from subarachnoid hemorrhage or inflammatory processes. FLAIR images in the horizontal plane were analyzed from the first M1-MCA appearance to the 10th image. We adopted the same scoring system in the previous paper [11]. The score was based on a rostrocaudal extension of HVS. Absence of HVS on 1 slice was rated 0 point. As 10 images were analyzed, resulting HVS ranged from 0 to 10 (Fig 1A). Patients were classified as high HVS (>5 slices of HVS on FLAIR) or low (≤5) group. Patients with one or more vessel segments observable in PCA P4 segment beyond the extent of filling seen in the contralateral PCA, were classified as PCA laterality positive (Fig 1B). Two readers (S.T.; stroke neurologist, >10 years of experience and Y.T.K.; neurosurgeon, >5 year-experience of stroke clinical practice) each graded the HVS and PCA laterality for each patient, independently and regraded by consensus if the grading differed.

10.1371/journal.pone.0309779.g001 Fig 1 A: representative case presentation of HVS; 31 year-old female had right MCA M1 proximal occlusion. MRI FLAIR image was performed at five hours after stroke onset. The figure shows eight slices of HVS on FLAIR. The patient was classified as high HVS group. B: representative case presentation of PCA laterality; 77 year-old male had left MCA M1 proximal occlusion. MRA was performed at 19 hours after stroke onset. The figure shows observable extended PCA P4 segment.

We compared CTPCI at baseline imaging, core and penumbra volumes at baseline and follow-up between high or low HVS group, and between PCA laterality positive or negative group. Further, we investigated neurological outcomes (modified Rankin Scale (mRS) at three months after stroke onset) of each group. The CTPCI is a continuous variable with lower value representing better collateral flow [6] and predicts slow core growth [14] and persistent penumbra [15]. The following equation was used to define the index: CTPCI = DT>6 /DT>2 × 100

Statistical analysis

Continuous variables are presented as median with interquartile range. Clinical characteristics were compared between high or low HVS group and with or without PCA laterality using Pearson’s chi-square test for categorical variables, or Wilcoxon’s rank sum test for continuous variables. Multiple regression analysis was performed with core volume at follow-up as a dependent variable, incorporating HVS, PCA laterality, occlusion site and thrombolysis as independent ones. All statistical analysis was done using STATA 15.0 (Stata Corp, College Station, Texas, USA), with significance level set at 0.05. The datasets generated for this study are available on request to the corresponding author.

Results

We reviewed 272 patients who had baseline CT perfusion imaging within 6 hours after stroke onset and follow-up MR perfusion imaging/angiography within 30 hours after stroke (Fig 2). We excluded patients with effective recanalization between baseline and follow-up imaging (n = 119), small vessel occlusion (n = 78), anterior/posterior cerebral, basilar artery occlusion (n = 20), and those with critical data unavailable (n = 6). We included 49 patients (Table 1); median age was 70 years old, 55% of them were male and 92% were independent (premorbid mRS 0─1). Sixteen (33%) patients had known or new-onset atrial fibrillation. NIHSS at baseline was a median of 15. Distribution of occlusion site was ICA (n = 26; isolated 10 (20%), tandem 16 (33%)), MCA M1 (n = 14, 29%) and M2 (n = 9, 18%) segment. All thirty-three (67%) patients who received thrombolysis completed treatment before the follow-up MRI. There were no patients with thrombectomy. Time from onset to baseline and to follow-up imaging were a median of 2.0 hours and 20 hours, respectively.

10.1371/journal.pone.0309779.g002 Fig 2 Patient enrolment.

10.1371/journal.pone.0309779.t001 Table 1 Clinical characteristics of all enrolled patients.

	Total population, N = 49	
Age, years old, median, IQR	70 [62─79]	
Sex, male, no. (%)	27 (55)	
Premorbid mRS 0─1, no. (%)	45 (92)	
Risk factors, no. (%)		
 Hypertension	26 (53)	
 Hyperlipidemia	21 (43)	
 Diabetes mellitus	9 (18)	
 Atrial fibrillation (known or newly onset)	16 (33)	
 Ischemic heart disease	7 (14)	
Pre-anticoagulant or antiplatelet treatment, no. (%)	10 (20)	
NIHSS at baseline, median, IQR	15 [13─19]	
Occlusion site, no. (%)		
 Internal carotid artery isolated occlusion	10 (20)	
    tandem occlusion	16 (33)	
 Middle cerebral artery M1 segment	14 (29)	
    M2 segment	9 (18)	
Thrombolysis, no. (%)	33 (67)	
Time from onset to baseline image, hours, median, IQR	2.0 [1.6─3.2]	
Time from onset to follow-up image, hours, median, IQR	20 [4.2─26]	
IQR; interquartile, mRS; modified Rankin Scale, NIHSS; National Institute of Health Stroke Scale

FLAIR image was not available in four patients because of severe motion artifacts. The remaining 45 patients were classified into high (n = 23) or low (n = 22) HVS groups (Table 2). Time from onset to MRI was a median of 20 hours [4.1─26] in the high HVS group, and 23 hours [7.2─26] in the low HVS group. Atrial Fibrillation was present in 11 patients (48%) in the high HVS group, compared to 5 (23%) in the low HVS group. Distribution of occlusion site was: 14 MCA and 9 ICA in the high HVS group, and 9 MCA and 13 ICA in the low HVS group. The high HVS group were more likely to have lower CTPCI (better collateral status) at baseline (median CTPCI in the high HVS group; 28% versus 38%, p = 0.001), smaller core volume at baseline (a median of 19 ml versus 58 ml, p<0.001) and follow-up (32 ml versus 109 ml, p = 0.004), more persistent penumbra volume at follow-up (68 ml versus 0 ml, p = 0.001) and more favorable neurological outcome (median mRS at three months; 3 versus 5, p = 0.03).

10.1371/journal.pone.0309779.t002 Table 2 Comparison of clinical characteristics between patients with high or low HVS and with or without PCA laterality.

	HVS	PCA laterality	
	High, n = 23	Low, n = 22	P-value	Positive, n = 22	Negative, n = 26	P-value	
Age, years old, median	75 [65─79]	64 [59─71]	0.06	70 [59─72]	70 [63─79]	0.29	
Sex, male, no. (%)	11 (48)	14 (64)	0.29	14 (64)	13 (50)	0.34	
Premorbid mRS 0─1, no. (%)	19 (86)	22 (96)	0.35	21 (95)	23 (88)	0.61	
Atrial fibrillation, no. (%)	11 (48)	5 (23)	0.08	8 (36)	8 (31)	0.68	
Time from onset to baseline CT, hours, median	2 [1.6─3.5]	2.2 [1.6─3.2]	0.72	2.1 [1.6─3.2]	2 [1.6─2.8]	0.61	
Time from onset to follow-up MRI, hours, median	20 [4.1─26]	23 [7.2─26]	0.51	19 [4.2─26]	20 [4.1─25]	0.73	
NIHSS at baseline, median	15	16	0.73	15	18	0.44	
  at follow-up	14	16	0.69	18	14	0.11	
MCA occlusion, no. (%)	14 (61)	9 (41)	0.18	7 (32)	15 (58)	0.07	
ICA occlusion, no. (%)	9 (39)	13 (59)	-	15 (68)	11 (42)	-	
CTP collateral index at baseline, median, %	28 [17─32]	38 [30─54]	0.001	34 [28─42]	31 [21─44]	0.59	
Baseline perfusion lesion, ml, median	117	139	0.61	145	108	0.27	
 Core volume	19	58	<0.001	39	32	0.47	
 Penumbra volume	98	66	0.048	99	74	0.14	
Follow-up perfusion lesion, ml, median	143	187	0.44	207	135	0.34	
 Core volume	32	109	0.004	116	37	0.02	
 Penumbra volume	68	0	0.001	34	56	0.27	
Thrombolysis, no. (%)	17 (74)	14 (64)	0.46	12 (55)	21 (81)	0.05	
mRS at three months, median	3 [2─5]	5 [3─6]	0.03	5 [3─6]	4 [3─6]	0.49	
CTP; computed tomography perfusion, HVS; hyperintense vessel sign, ICA; internal carotid artery, MCA; middle cerebral artery, mRS; modified Rankin Scale, NIHSS; National Institute of Health Stroke Scale, PCA; posterior cerebral artery

One patient with a history of previous PCA occlusion was excluded, so 48 patients were classified as PCA laterality positive (n = 22) or negative (n = 26) (Table 2). The positive group had a higher core volume at follow-up imaging than the negative group (median 116 ml versus 37 ml, p = 0.02) and larger core growth (68 ml versus 4.5 ml, p = 0.02). There were no significant baseline imaging differences between groups, however the rate of ICA occlusion in the PCA laterality positive group was numerically higher, and this approached statistical significance (68%, versus 42% for the negative group; p = 0.07). There was no significant difference in neurological outcome between the two groups. Interestingly, there was a borderline significantly lower rate of thrombolysis in those with PCA laterality positive group (55%, v 81% in the PCA laterality negative group; p = 0.05). Of 22 patients with PCA laterality positive, 12 (55%) had high HVS compared to 10 (38%) in the PCA laterality negative group.

In the multiple regression analysis, PCA laterality positive was related to larger core volume at follow-up, while high HVS was associated with the smaller one. (S1 Table).

Discussion

We identified 23 patients with prominent HVS on FLAIR image performed a median 20 hours after stroke. The high HVS group showed lower CTPCI suggesting better collateral status. Consistent with this, these patients also had smaller initial core volume, more persistent penumbra at follow-up imaging and more favorable neurological outcomes. We identified 22 patients with positive PCA laterality. Counter to the hypothesis that PCA laterality would be associated with better collaterals and therefore better prognosis, there were significantly larger core growth and larger follow up infarct core volumes in this group, and we did not find other markers of favorable collateral status such as more favorable CTPCI, or better neurological outcome. These findings suggest better performance of high HVS for identification of those with good collateral status than PCA laterality positivity. This may reflect the fact that PCA-MCA collaterals make a smaller contribution to MCA perfusion than ACA-MCA collaterals [16], however as discussed below, other factors may also have influenced this result.

Prominent HVS within 4.5 hours after stroke has been reported to represent good collateral status and favorable neurological outcomes [10, 11]. We showed similar results in patients with a median 20 hours after stroke onset. The subjects in previous studies were those with MCA (M1 or M2 segment) occlusion, but we found prominent HVS not only in those with isolated MCA occlusion but also in those with tandem or isolated ICA occlusion. ICA occlusion typically leads to whole poor collateral status because of Willisian collateral failure. However, 20% of the total population in the DAWN trial and 37% of those in the DEFUSE 3 trial had ICA occlusion, but showed good collateral status 16–24 hours after stroke [1, 2]. Patients with chronically developed ICA occlusion may be more likely to have better collateral than those with more abrupt occlusion [17, 18]. Such patients may be likely to have prominent HVS even in a late time window.

The clinical implication is that HVS appears to remain useful for interpretation of collateral status, beyond 4.5 hours after stroke onset. Small ischemic core may be difficult to recognize on DWI image and the volume may not be immediately calculated. Prominent HVS suggesting good collateral supply is easy to recognize on FLAIR image, and in addition to clinical-core mismatch, it may assist decision-making to progress to EVT, in hospitals where acute perfusion imaging analysis is not available.

We found larger core growth and final infarct core volumes in the PCA laterality positive group and did not find better CTPCI collateral status or more favorable neurological outcome. There were several possible reasons for this. Whereas subjects in previous studies had MCA M1 segment occlusion [9, 12], we also included patients with ICA occlusion, and ICA was the major occlusion site in the positive group. PCA laterality may be more common in those with ICA occlusion since typically these patients will have poorer ACA-MCA collaterals, due to reduced flow to the ipsilateral ACA. Therefore, there is likely to be lower pressure within the occluded MCA arterial tree, driving higher PCA-MCA collateral flow. However, this confounds the findings regarding PCA laterality since the group with ICA occlusion will do worse. We did not have sufficient numbers of patients to be able to analyse those with and without ICA occlusion separately. A further complicating factor was that the rate of thrombolysis was higher in the group without PCA laterality. Intravenous thrombolysis has previously been reported to reduce core growth rate in patients with large vessel occlusion and non-recanalisation [19], implicating thrombolysis working on distal microvasculature and reducing microvenous thrombosis [20]. Therefore, the higher rate of thrombolysis may also contribute to higher rates of favorable outcome in the PCA laterality negative group. Overall, these factors suggest a high degree of caution in interpretation of the data regarding PCA laterality.

Strengths of this study are that we evaluated collateral status at baseline imaging with CTPCI as continuous variables in each comparison of HVS or PCA laterality. We assessed ischemic core and penumbra volume with baseline and follow-up perfusion imaging, and all perfusion images were analyzed with the same software (MIStar). There are several limitations. The first is that the sample size was unavoidably small, because of the retrospectivity, and strict inclusion criteria. Secondly, thrombolysis may have affected the collateral status on follow-up MRI, although we did exclude patients with effective recanalization between baseline and follow-up imaging to try to avoid this.

Conclusions

Prominent HVS on FLAIR image in patients with ICA or MCA occlusion up to 30 hours after stroke was associated with good perfusion imaging collateral status, small infarct core volume, persistence of ischaemic penumbra, and favorable clinical outcome. The information of prominent HVS may assist a decision of EVT in a late time window at hospitals where perfusion imaging analysis is not available.

Supporting information

S1 Table Multiple regression analysis of core volume at follow-up image.

(DOCX)

10.1371/journal.pone.0309779.r001
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Stephan Meckel
https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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PONE-D-24-11660Collateral assessment on magnetic resonance imaging/angiography up to 30 hours after stroke onsetPLOS ONE

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5. Review Comments to the Author

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Reviewer #1: This paper is a valuable report that focuses on two collateral flow indicators, HVS and PCA laterality, and compares them with two perfusion images.

Although relatively old, this dataset is unique because it is now ethically difficult not to perform thrombectomy in patients with acute onset large vessel occlusion. Another feature of the dataset is the relatively large number of tandem occlusions.

It is very interesting in that the classically known HVS is influencing recanalisation therapy decision making, but several areas require further consideration:

Major comments

1. It seems strange that there were no patients in the dataset who had undergone mechanical thrombectomy (MT), as there were already 5RCTs on MT in 2015 when this study was conducted. The inclusion criteria seem to include patients who would be good candidates for MT. Please clarify if any of the excluded patients had undergone MT or if there were any study design or institutional limitations.

2. In this report, it was reported that HVS and PCA laterality were assessed by two readers. Does this mean that two readers evaluated different patients or two readers evaluated the same patients, and if the latter, how were the discrepant cases handled?

3. Prestroke mRS should be reported because of the prognostic impact in the HVS high group and the HVS low group. The aetiology of stroke (e.g. TOAST classification) should also be included as the dataset is characterised by a relatively high number of ICA tandem occlusions. Time from onset to imaging should also be included in the table, as it may be related to HVS and PCA laterality.

Minor comments

1. Please describe the management of patients with M3 or more distal occlusions.

2. The scoring method for HVS seems to be the same as in ref. 11; it is advisable to add this to the METHOD.

Reviewer #2: This is a retrospective study of 49 stroke patients with ICA and/or proximal MCA occlusion with unfavorable recanalization, investigating the relationship between the hyperintense vessel sign (HVS) on FLAIR and PCA laterality on MRA, and their impact on stroke outcomes. The study found that a prominent HVS is associated with a smaller core volume and a larger penumbra volume at follow-up, and better clinical outcomes. In contrast, PCA laterality did not show significant differences in penumbra volumes or outcomes. In fact, it was associated with larger infarct volume at follow-up. The results suggest that HVS is a reliable indicator of good collateral status and favorable prognosis in late-window stroke patients, while PCA laterality does not correlate as strongly with these outcomes.

While the association between collateral status, good functional outcomes, and these radiographic markers was previously reported, those studies only evaluated patients within 4.5 hours from the onset of the stroke. The originality of this study lies in its examination of the same associations within a later time window, between 4.5 and 30 hours after stroke onset.

The clinical significance of these study results lies in the confirmed association between good collateral and penumbral status and the HVS. This finding suggests that HVS could serve as a surrogate marker for perfusion scans. Consequently, HVS could aid in the decision-making process for thrombectomy in patients with large vessel occlusion who are scanned using MRI/MRA but are unable to receive gadolinium contrast for perfusion scans due to medical conditions such as renal failure.

I found one major point of revision that may increase the study’s validity. The authors separated the 49 patients into two groups based on high versus low HVS, and positive versus negative PCA laterality. Since the same patient cohort was categorized using two different criteria, there is likely significant overlap between the groups. For instance, it is plausible that many patients with high HVS also exhibited positive PCA laterality—a correlation previously noted in the literature (PMID 23532013). Therefore, considering the strong correlation between these variables, an adjusted analysis may provide more insight. I recommend conducting an adjusted analysis with the core volume on follow-up scans (and other clinically meaningful aspects) as the dependent variable, incorporating the presence of HVS, PCA laterality, and clot location, especially since the positive PCA laterality group reportedly had a higher incidence of ICA occlusions. This approach would help clarify the independent effects of each variable on patient outcomes, given that the current results are based on unadjusted comparisons.

Here is the suggested minor edit points:

1) Page 2, Line 21, “a late time window up to 30 hours”. I assume the “late time window” means between 4.5h and 30h from the onset of the stroke. Please define the starting point of this “late time window” for clear understanding.

2) Page 2, Line 34, “TIMI grade”. I think TIMI was the typo of modified TICI score. However, if this was legitimate, please provide a reason why the scoring system for coronary revascularization was used to evaluate the result of cerebral thrombectomy.

3) For readers who are not familiar with MIStar, please consider adding a brief description of what Delay Time is and how it differs from Mean Transit Time and Time to Peak.

Reviewer #3: The authors evaluated the association between hypertensive vessel sign on FLAIR imaging (HVS) or PCA laterality on MRA within 30 hours form onset and outcome They showed that prominent HVS in later time was significantly associated with small core, and persistent penumbra volume, and favorable outcome. This study suggested useful imaging markers to predict short term outcome in patients with LVO in anterior circulation presented beyond 4.5 hours; however, there are some questions and comments about contents of the manuscript.

1.When considering the association between HVS and clinical outcome, the possibility of loss of HVS due to the completion of infarct at the same territory should be considered. This study showed the association between high score of HVS and good clinical outcome, but the volume of ischemic core was significantly larger in the low HVS group both at the initial visit and at follow-up. Significant and strong correlation between the low score of HVS and the large ischemic core is not surprising. What is the significance of using HVS rather than initial ischemic core as a predictor of clinical outcome? To elucidate the significance of HVS on clinical outcome, the effect of infarct core volume should be considered.

2.If the follow-up imaging performed within 30 hours after onset (median 20 hours) was used as surrogate for initial assessment of late presenting stroke, as the author mentioned as the limitation of study, the effect of acute treatment, especially intravenous thrombolysis, could not be ignored. Moreover, in this study, the final core volume at the follow-up would correspond to the initial ischemic core in late presenting stroke. If this study was designed for late presenting stroke, true ischemic core measured after follow-up visit should be analyzed. Similarly, clinical baseline parameters including initial NIHSS, were less meaningful. The author should present the NIHSS score obtained at follow-up.

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10.1371/journal.pone.0309779.r002
Author response to Decision Letter 0
Submission Version1
27 Jun 2024

We thank the reviewers for their insightful comments, which have helped us significantly improve our manuscript. We hope that our revised manuscript is acceptable for publication.

Attachment Submitted filename: Response to reviewers.docx

10.1371/journal.pone.0309779.r003
Decision Letter 1
Meckel Stephan Academic Editor
© 2024 Stephan Meckel
2024
Stephan Meckel
https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Submission Version1
20 Aug 2024

Collateral assessment on magnetic resonance imaging/angiography up to 30 hours after stroke onset

PONE-D-24-11660R1

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10.1371/journal.pone.0309779.r004
Acceptance letter
Meckel Stephan Academic Editor
© 2024 Stephan Meckel
2024
Stephan Meckel
https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
22 Aug 2024

PONE-D-24-11660R1

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==== Refs
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